Signaling through the platelet integrin, alphaIIb/beta3, is a key element in the "final common pathway" leading to platelet aggregation. Indeed, a proven strategy to pharmacologically prevent platelet aggregation, and the subsequent thrombus formation which can lead to ischemic coronary and carotid disease, involves blockade of alphaIIb/beta. The focus of this Phase I application is to develop a novel strategy for affecting alphaIIb/beta3 function by targeting specific steps in integrin-mediated signaling events rather than by targeting extracellular binding events. Recent research has highlighted the important role played by integrin cytoplasmic domains [cytodomains] in integrin function. In particular the direct interaction of cytodomains with intracellular proteins appears to be functionally significant. The applicants postulate that compounds capable of inhibiting such interactions will disrupt alphaIIb/beta3 function, thus preventing platelet aggregation and have the potential to be a powerful new class of anti-thrombotics. Phase I of this proposal aims to establish novel methods for screening for inhibitors of integrin cytodomain/protein interactions, with implementation of high-throughput screens being a Phase II goal. In the long term, the applicants hope to determine whether inhibitors of alphaIIb/beta3 signal transduction will offer improved therapy for the large population of people afflicted with ischemic cardiovascular disease. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE